As chemotactic substances that induce chemotaxis and topical infiltration of leukocytes such as neutrophil, monocyte and the like, there are classical chemotactic factors such as complement catabolites C3a and C5a, arachidonate metabolites such as leukotriene B4 and the like, platelet-activating factor, bacterium-derived formyl peptide and the like. These are secondary products mainly associated with tissue lesions. On the other hand, the presence of a series of cytokines that are produced by new expression of gene and responsible for the induction and activation of particular leukocyte, namely, chemokines, was verified by interleukin (IL-8) (CXCL8) purified and gene cloned by Matsushima et al. in 1987 (see. e.g., Proc. Natl. Acad. Sci. USA, 84, 9223-9237 (1987) and J. Exp. Med., 167, 1883-1893 (1988)).
There are 42 chemokines identified to the present, and chemokines are classified into four subgroups based on the characteristics of their amino acid sequences. That is, C chemokine, CC chemokine, CXC chemokine and CX3C chemokine.
XCL1 belonging to C chemokine shows chemotactic activity for T cells and NK cells.
CC chemokine shows chemotactic activity for monocytes other than neutrophils, lymphocytes, Langerhans cells, dendritic cells, eosinophils, mast cells and basophils. Furthermore, CXC chemokine mainly acts on chemotaxis of neutrophils as represented by the action of CXCL8, and CX3C chemokine mainly acts on chemotaxis of NK cells. These chemokines exhibits their actions by binding to G-protein-coupled receptors (chemokine receptors) and 18 chemokine receptors have been identified to the present (see e.g., CELL TECHNOLOGY, 17, 1022-1029 (1998) and Immunity, 12, 121-127 (2000)).
Therefore, a substance that inhibits the binding between chemokine and its receptor suppresses selective chemotaxis and activation of leukocytes, and is considered to be useful as a pharmaceutical product for the prophylaxis or treatment of acute and chronic inflammatory diseases including allergic diseases and the like.
Particularly, one of the pathological characteristics of asthma, sinusitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease, rheumatoid arthritis and the like is eosinophil infiltration into the inflammatory tissue. Therefore, eosinophils are considered to play a key role in the onset, progress and retention of these diseases.
It is known that CCR3, one of the CC chemokine receptors, plays an important role in the chemotaxis to inflammatory lesion and activation and the like of eosinophils, and CCR3 is expressed not only in eosinophils but also in inflammatory cells such as mast cells, basophils, dendritic cells, Th2 cells and the like (J. Clin. Invest., 99(2), 178-184 (1997), J. Exp. Med., 190(2), 267-280 (1999), J. Clin. Invest., 100(5), 1137-1143 (1997), Science, 277, 5334, 2005-2007 (1997), and Pharmacol. Rev., 52(1), 145-176 (2000)). In asthma and atopic dermatitis models of CCR3 gene knockout mouse, eosinophils infiltration into the lung and skin, and airway hypersensitivity are suppressed as compared to wild-type mouse (J. Clin. Invest., 109(5), 621-628 (2002)).
It is also known that infiltration of activated eosinophils is observed in nasal polyp tissue extract of sinusitis, and CCL11, CCL13 and CCL24, which are selective and strong ligands of CCR3, significantly increase therein (J. Immunol., 163(3), 1545-1551 (1999)). Moreover, CCR3 positive mononuclear cells significantly increase in peripheral blood and synovial fluid of rheumatoid arthritis patients as compared to healthy subjects (Arthritis Rheum., 44(5), 1022-1032 (2001)).
In consideration of the above, a compound having affinity for CCR3 is expected to be useful as a pharmaceutical product for the prophylaxis or treatment of immune and inflammatory diseases.
In addition, for example, the following patent references regarding therapeutic agents for immune and inflammatory diseases, which show affinity for chemokine receptors, have been published. WO97/24325 discloses diphenylmethane derivatives and WO98/25617 discloses arylpiperazine derivatives, as compounds having affinity for chemokine receptors, WO98/02151, WO98/04554 and WO00/34278 disclose tricyclic heteroaromatic derivatives and the like having affinity for chemokine receptors, WO99/55324 and WO99/55330 disclose phenylalanine derivatives and the like having affinity for chemokine receptors, WO00/58305 discloses piperazine derivatives and the like having affinity for chemokine receptors, and WO00/31033, WO00/53600, WO01/14333, WO02/66460 and WO02/88111 disclose piperidine derivatives and the like having affinity for chemokine receptors. In addition, WO02/18335 discloses cyclic amine derivatives having a CCR3 antagonistic action. In addition, WO02/26722, WO02/26723, WO03/82292, WO03/82294, WO03/82861, WO03/82862, WO03/82295, WO03/82863, WO03/99287 and WO03/99798 disclose morpholine derivatives and the like having affinity for chemokine receptors. However, these compounds do not have the structural characteristics that the compound of the present invention to be mentioned below shows as a preferable embodiment (i.e., compounds having sulfur atom on alkylene chain having morpholine ring via methylene amide).
Since a clinically effective low-molecular-weight compound having CCR3 affinity has not bee reported to date, a CCR3 antagonist having a different structure is expected to be a pharmaceutical product for the treatment or prophylaxis of acute and chronic inflammatory diseases and the like, including immune and allergic diseases.
EP243959A discloses a racemate of the formula (26) shown below, which is useful as a synthetic intermediate for the compound of the present invention.